The long range goal is intervention to delay or prevent cognitive decline associated with unsuccessful aging, in order to improve the health and well-being of older Americans. The incidence of Alzheimer's disease is projected to increase dramatically, with the greatest prevalence in women. Synaptic loss contributes to memory impairments and estrogen (E2) promotes synaptogenesis and memory. Thus, E2 treatment could have a major impact on public health. However, the efficacy of E2 is greatly reduced if therapy occurs several years after the onset of menopause, suggesting a temporally limited therapeutic window. Evidence indicates estrogen receptor (ER) expression and ER polymorphisms contribute to a variety of hormone sensitive diseases, including cognitive decline. We hypothesize that differential expression of ER1 and ER2 interacts with the level of E2 to contribute to 1) the etiology of age-related memory deficits, 2) loss of E2 mediated synaptogenesis, and 3) the closing of the E2 therapeutic window. Aim 1 will combine aging ER1 and ER2 knockout mice with viral vectors to influence ER expression and systematically perform behavioral, molecular, and electrophysiological assays to test the hypothesis. Aim 2 will employ hippocampal viral delivery vectors to increase or decrease ER1 or ER2 in young, middle-age, and aged rats, and will use behavioral and molecular assays to test the hypothesis that shifting the ratio of ER1/ER2 expression rejuvenates hippocampal function. Aim 3 will employ viral vectors to alter the expression of ER1 or ER2, and will test the hypothesis that ER expression contributes to age-related changes in rapid E2 signaling. Knockout mice and viral vector gene delivery provide novel approaches to test the hypothesis that ER expression is a contributing factor for hippocampal aging. Together, these studies will determine whether altering the level of ER1 or ER2 expression is important for age-related memory decline, E2-induced synaptogenesis, and closing of the E2 therapeutic window, and will provide the groundwork for development of therapies to slow or prevent cognitive decline associated with aging and age-related diseases.